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July 11, 2011
A Detailed Look at Ovarian Cancer
An analysis of genomic changes in ovarian cancer now provides the most comprehensive and integrated view of cancer genetics for any cancer type to date.
Last year, nearly 22,000 women nationwide were diagnosed with ovarian cancer and about 14,000 women died from it. Ovarian cancer is a complex disease that can arise from various molecular problems. A comprehensive catalog of these potential causes could help researchers develop more targeted and effective treatments. Scientists in The Cancer Genome Atlas (TCGA) Research Network set out to create such a catalog. TCGA is a collaborative effort funded by NIH's National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI).
The researchers focused on serous adenocarcinoma, the most prevalent form of ovarian cancer, accounting for about 85% of all ovarian cancer deaths. The researchers built upon an approach they used in 2008 to characterize the genome of the most common form of brain cancer. They performed whole-exome sequencing, which examines the protein-coding regions of the genome, on an unprecedented 316 tumors. They also completed other genomic characterizations on these tumors, along with another 173 specimens. The results appeared in the June 30, 2011, issue of Nature.
The researchers found that mutations in a single gene, TP53, were present in more than 96% of the tumors. TP53 encodes a tumor suppressor protein that normally prevents cancer formation. Two other genes, BRCA1 and BRCA2, were mutated in 22% of the tumors. There were also less frequent mutations in 7 other genes.
The scientists found additional genetic anomalies as well. They identified 113 significant DNA copy number aberrations — differences in the number of copies of specific DNA regions. Modifications to promoter regions, which are known to affect gene expression, were found in 168 genes.
The researchers were able to identify distinct subtypes of the disease. They also detected patterns of gene expression that predict patient survival. Patterns for 108 genes were associated with poor survival and 85 genes with better survival.
To identify opportunities for targeted treatment, the investigators searched for existing drugs that might inhibit the over-expressed genes they identified. They found 68 genes that could be targeted by known compounds, some of which are already approved by the U.S. Food and Drug Administration.
“The integration of complex genomic data sets enabled us to discover an intricate array of genomic changes and validate one specific change that occurs in the vast majority of all ovarian cancers,” says lead author Dr. Paul T. Spellman of the Lawrence Berkeley Lab.
“The new knowledge of the genomic changes in ovarian cancer has revealed that the molecular catalysts of this disease are not limited to small changes affecting individual genes,” says NCI Director Dr. Harold E. Varmus. “Also important are large structural changes that occur in these cancer genomes. Cancer researchers can use this comprehensive body of information to better understand the biology of ovarian cancer and improve the diagnosis and treatment of this dreaded disease.”